Alzheimer's disease is the most common form of dementia. It is a neurological disease characterized by loss of mental ability, severe enough to interfere with normal activities of daily living. Alzheimer's disease usually occurs in old age, and is marked by a decline in cognitive functions such as remembering, reasoning, and planning. The median survival time for affected patients is approximately 8 years from the onset of symptoms (Coyle, J., Kershaw, P., 2001. Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic receptors: effects on the course of Alzheimers disease. Biol. Psychiatry. 49, 289-299). Galantamine is a tertiary alkaloid and a reversible, competitive acetyl cholinesterase inhibitor (Zarotsky, V., Sramek, J. J., Cutler, N. R., 2001. Galantamine hydrobromide: an agent for Alzheimer's disease. Am. J. Health-Syst. Pharm. 60, 446-452). Galantamine is effective and well tolerated for symptomatic treatment of Alzheimer's disease; and improves cognition, global function and daily life activities of the patients (Scott, L. J., Goa, K. L., 2000. Galantamine: a review of its use in Alzheimer's disease. Drugs. 60, 1095-1122; Corey-Bloom, J., 2003. Galantamine: a review of its use in Alzheimer's disease and vascular dementia. Int. J. Clin. Pract. 57, 219-223).
At present, galantamine is available in the market as tablet or oral solution. Oral administration of galantamine is followed by side effects like abdominal pain, nausea, and diarrhea. Therefore, an alternative way of galantamine administration could be helpful for the success of therapy.
Transdermal drug delivery system (TDDS) is advantageous to minimize the gastrointestinal side effects such as nausea and vomiting, which are the most common adverse events leading even to discontinuation of treatment. TDDS offers benefits such as producing sustained and controlled plasma drug concentration, enhancing bioavailability and bypassing first-pass metabolism. Despite these advantages of TDDS, its use is often limited due to the outermost layer of the skin, stratum corneum. Although this layer is only 20-25 μm thick, it provides a potential barrier to the penetration of many compounds and poses a major problem for therapeutic TDDS (Thomas, B. J., Finnin, F. C., 2004. The transdermal revolution. Drug Discov. Today. 9, 697-703. Walters, K. A., Walker, M., Olejnik, O., 1987. Non-ionic surfactant effects on hairless mouse skin permeability characteristics. J. Pharm. Pharmacol. 40, 525-529).
Various approaches could be utilized to overcome the impermeability of skin. Among these approaches, chemical enhancers are commonly employed in the TDDS to facilitate the penetration of the administered drug (Williams, A. C., Barry, B. W., 2004. Permeation enhancers. Adv. Drug Deliver. Rev. 56, 603-618). It is well known that the enhancing properties of chemical enhancers depend on the physicochemical properties of drugs and other formulation components. In the matrix based TDDS, especially drug in adhesive (DIA) type, pressure sensitive adhesive (PSA, hereinafter referred to as “adhesive”) fulfills both the function of adhesion to skin, and serves as formulation foundation. Compatibility among drug, adhesive and enhancer as well as the adhesive property must be considered before the selection of appropriate adhesive.
U.S. Pat. No. 5,700,480 has disclosed a transdermal delivery system, which comprises a reservoir layer containing galantamine, a plasticizer, and a polyacrylate (for example, acrylate copolymer/methacylate copolymer) as an adhesive. The transdermal delivery system according to U.S. Pat. No. 5,700,480 shows very low penetration, i.e., about 2.7 μg/cm2/hr. In order to address such a problem and make drug-loading higher, US Patent Publication No. 2007/0104771A1 has disclosed a transdermal delivery system, which comprises a drug reservoir containing an acrylate polymer having polar funtional monomer component, more than 10% by weight of galantamine, and a permeation enhancer for delivering the galantamine at a flux of greater than 4.5 μg/cm2/hr. However, the transdermal delivery system according to US Patent Publication No. 2007/0104771A1 has the disadvantage that the flux thereof is still low, i.e., 11.35 μg/cm2/hr in maximum (Table 2).